Inflatable devices for tumor treatment

ABSTRACT

Implantable devices for treatment of proliferative disorders are described. In one aspect, the invention provides an implantable apparatus for treating a proliferative disorder in a patient. The device comprises a treatment fluid receptacle for receiving a treatment fluid, an inflatable balloon having a balloon body, a catheter connected between the treatment fluid receptacle and the balloon and defining a fluid flow path therebetween, and a diffusion barrier disposed in the fluid flow path between the treatment fluid receptacle and the balloon. Methods for treating proliferative disorders with the devices are also disclosed.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 08/307,165,filed Sep. 14, 1994, now U.S. Pat. No. 5,611,767, which is acontinuation of U.S. Ser. No. 07/715,923, filed Jun. 14, 1991, now U.S.Pat. No. 5,429,582, the contents of which are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

Treatment of proliferative disorders has become increasinglysophisticated in recent years, and improvements in surgical,chemotherapeutic and brachytherapeutic techniques have led to betteroutcomes in patients suffering from such disorders. The need forimproved devices for administration of chemotherapy and brachytherapyhas resulted in a number of new devices capable of delivering one ormore treatments to proliferative disease sites, such as tumors. One suchdevice is described in U.S. Pat. No. 5,429,582 to Williams, whichdiscloses an inflatable device for multi-modal therapy of tumors.Nevertheless, improved devices for treatment of proliferative disordersare needed.

SUMMARY

This invention provides improved devices for the treatment of tumors andother proliferative disorders in a patient in need of such treatment,and methods of treating proliferative disorders using such devices.

In one aspect, the invention provides an implantable apparatus fortreating a proliferative disorder in a patient. The device comprises atreatment fluid receptacle for receiving a treatment fluid, aninflatable balloon having a balloon body, a catheter connected betweenthe treatment fluid receptacle and the balloon and defining a fluid flowpath therebetween, and a diffusion barrier disposed in the fluid flowpath between the treatment fluid receptacle and the balloon.

In certain embodiments, the treatment fluid receptacle has a smallvolume and is adapted to be implanted subcutaneously in the body of thepatient. In certain embodiments, the device further includes a malleableelement. In certain embodiments, the diffusion barrier is a narrow flowsegment. In certain embodiments, the balloon has a substantiallyspherical shape when inflated. In other embodiments, the balloon has asubstantially ovoid shape when inflated. In some embodiments, theballoon is secured to the catheter at substantially a single point onthe balloon body. In other embodiments, the balloon is secured to thecatheter at a plurality of points on the balloon body. In certainembodiments, the balloon has an irregular shape when inflated.

The balloon body can be substantially impermeable to the treatmentfluid, while in other embodiments, the balloon can comprise asemipermeable membrane. In certain embodiments, the treatment fluidreceptacle can be flushed with a flushing fluid without substantiallyexpanding the balloon. In some embodiments, the balloon is secured tothe catheter such that the balloon maintains a pre-selected shape duringinflation. In preferred embodiments, the malleable element, if present,does not interfere with NMR measurements.

In certain embodiments, the balloon comprises a double-walled balloon ora triple-walled balloon. In some embodiments, the proliferative disorderis a brain tumor. In certain embodiments, the balloon is adapted forplacement in a cavity left by surgical removal of a tumor from thepatient. In other embodiments, the balloon is adapted for placement in anatural body cavity. In preferred embodiments, the balloon is filledwith a treatment fluid. In certain embodiments, the treatment fluid is aradioactive fluid. In some embodiments, the treatment fluid hassubstantially physiological tonicity.

In certain embodiments, the apparatus further comprises a secondtreatment fluid receptacle. In certain embodiments, the second treatmentfluid receptacle fluidly communicates with a volume between inner andouter balloon walls.

In another embodiment, the invention provides an implantable apparatusfor treating a proliferative disorder in a patient. The implantableapparatus includes a treatment fluid receptacle for receiving atreatment fluid, an inflatable balloon having a balloon body; a catheterconnected between the treatment fluid receptacle and the balloon anddefining a fluid flow path therebetween; and a diffusion barrierdisposed in the fluid flow path between the treatment fluid receptacleand the balloon, and in which the balloon is secured to the cathetersuch that the balloon maintains a pre-selected shape during inflation;and in which the treatment fluid receptacle is adapted to be flushedwith a small volume of a flush fluid.

In another aspect, the invention provides a method for treating aproliferative disorder, such as a tumor, in a patient. The methodincludes the steps of implanting in the patient's body an inflatabletreatment apparatus, in which the apparatus includes a treatment fluidreceptacle for receiving a treatment fluid; an inflatable balloon havinga balloon body; a catheter connected between the treatment fluidreceptacle and the balloon and defining a fluid flow path therebetween;and a diffusion barrier disposed in the fluid flow path between thetreatment fluid receptacle and the balloon; and introducing a treatmentfluid into the treatment fluid receptacle such that the balloon isinflated; such that the proliferative disorder is treated.

In certain embodiments, the method includes the further step of flushingthe treatment fluid into the balloon.

In another aspect, the invention provides a method for treating aproliferative disorder in a patient. The method comprises determining acharacteristic of a cavity in the patient's body, the characteristicbeing selected from the group consisting of volume, shape, or adimension; selecting an inflatable balloon suitable for placement in thecavity, the balloon including a balloon body. The method includes thefurther steps of implanting in the cavity an inflatable treatmentapparatus comprising a treatment fluid receptacle for receiving atreatment fluid; the inflatable balloon; a catheter connected betweenthe treatment fluid receptacle and the balloon and defining a fluid flowpath therebetween; and a diffusion barrier disposed in the fluid flowpath between the treatment fluid receptacle and the balloon. The methodfurther includes the step of introducing a treatment fluid into thetreatment fluid receptacle such that the balloon is inflated, such thatthe proliferative disorder is treated.

In certain embodiments, the method includes, prior to the implantingstep, the further step of assembling the inflatable treatment apparatus.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic cross-sectional view of one embodiment of thetreatment devices of the invention.

FIGS. 2A and 2B show cross-sectional views along the line 2--2' ofembodiments of the catheter of the invention.

FIG. 3 is a schematic cross-sectional view of a double-balloonembodiment of a treatment device of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The ability to selectively deliver therapy to a target organ or site,e.g., a tumor, is of great value to physicians. Accordingly, theinvention provides methods and apparatuses suitable for delivery of oneor more therapeutic modalities in a selective fashion.

For convenience, certain terms employed in the specification, examples,and appended claims are collected here.

The term "proliferative disorder" is recognized in the art, and, as usedherein, refers to a disorder including or characterized by rapid orabnormal cell growth or proliferation. Exemplary proliferative disordersinclude, but are not limited to, tumors, e.g., cancerous tumors;restenosis, e.g., regrowth of smooth muscle cells of blood vessels afterangioplasty; abnormal angiogenesis; hyperplasia, e.g., benign prostatichyperplasia; and the like.

The term "treatment fluid," as used herein, refers to a fluid used fortherapy of a proliferative disorder. Treatment fluids includechemotherapy fluids such as are conventional in the art, as well asfluids suitable for radiation therapy (brachytherapy), e.g., fluidscomprising a radioisotope useful in treatment of proliferativedisorders.

The term "treatment fluid receptacle," as used herein, refers to areceptacle or chamber adapted for receiving a treatment fluid. Treatmentfluid receptacles are known in the art, and include injection ports andsimilar devices. A "small-volume" treatment fluid receptacle has avolume or hold-up less than conventional treatment fluid receptacles,e.g., less than about 5 ml, more preferably less than about 2 ml, andstill more preferably less than 1.5 ml. Thus, treatment fluidreceptacles having little dead space or low hold-up volumes aregenerally preferred for use in the methods and devices of the invention.Particularly preferred treatment fluid receptacles can be flushed with asmall volume of flush fluid, as described in more detail below.

The term "diffusion barrier," as used herein, refers to an elementadapted for decreasing or preventing diffusion or flow of fluid from aballoon into the catheter lumen or treatment fluid receptacle of thesubject inflatable treatment device.

A balloon that maintains a "substantially constant shape," as usedherein, refers to a balloon that maintains substantially a single shapeor profile over a range of inflation sizes. Thus, for example, a balloonthat maintains a substantially spherical shape upon inflation has agenerally spherical shape over a range of inflation sizes, from lowinflation to full inflation, and does not generally change shape asinflation is increased or decreased. It will be understood by theskilled artisan, however, that the initial shape of a balloon can bechosen to minimize the size or profile of the deflated balloon, e.g., toease insertion of the balloon into a body cavity. Thus, a balloon canhave an initial shape different from a "substantially constant shape,"and still assume a "constant shape" after partial inflation. A"predetermined shape" refers to a shape that can be selected by thepractitioner before balloon insertion, e.g., a shape chosen to ensurecompliance of the balloon body to a selected surface, e.g., a cavitysurface.

The term "narrow flow segment", as used herein, refers to a narrowed orrestricted portion of a flow path. Preferably, a narrow flow segment hasa flow passage sufficiently small to slow or prevent significant flow ordiffusion of a fluid through the passage without application ofpressure.

The term "malleable element," as used herein, refers to an element,e.g., a wire, that is malleable or flexible, i.e., capable of beingshaped by bending, flexing, pressing and the like, and maintaining,temporarily or permanently, the shape thus provided. In preferredembodiments, a malleable element can be shaped by hand, e.g., by asurgeon performing a surgical procedure, to impart a selected shape tothe malleable element and to the catheter of which it forms a part.

The term "flushing fluid," as used herein, refers to fluid that can beused to flush, rinse, or wash a flow portion of an inflatable treatmentdevice. A flushing fluid can be inert, e.g., a saline solution, or canitself be a treatment fluid. In general, an inert flushing fluid ispreferred.

The term "patient," as used herein, refers to an animal in need oftreatment for, or susceptible to, a proliferative disorder. In preferredembodiments, the patient is a warm-blooded animal, more preferably amammal, including humans and non-human mammals such as dogs, cats, pigs,cows, sheep, goats, rats, and mice. In a particularly preferredembodiment, the subject is a human.

The inflatable treatment devices of the invention provide certainadvantages over devices known in the art. The subject devices areadaptable to a wide variety of therapeutic treatments, and are simpleand safe to use. In general, the devices are implanted in a patient'sbody such that the balloon is in close proximity to the site to betreated, e.g., the tumor, blood vessel, and the like. In one embodiment,the balloon is placed in a natural body cavity or a cavity resultingfrom surgical removal or displacement of tissue, e.g., surgicaldebulking of at least a portion of a tumor, or angioplasty to displaceor compress a growth of a blood vessel.

Thus, for example, FIG. 1 shows a cross-sectional view of an inflatabledevice of the invention when implanted in a body cavity. In thisembodiment, the device 10 is implanted below the skin 12 in a cavity 13formed in the patient's tissue 14. The device 10 includes an injectionport 20 which has an elastomeric seal 22 secured thereto. A balloon 24is disposed in the cavity 13 and fluidly connected to the injection port20 through a catheter 26, which includes a malleable element 28. Theballoon is filled with a treatment fluid 30, which fluid is preventedfrom flowing back from the balloon 24 into the catheter 26 by adiffusion barrier 32.

In certain embodiments, a treatment fluid receptacle is implantedsubcutaneously, permitting ready injection of a treatment fluid whileallowing healing of a surgical incision. Treatment fluid receptaclessuitable for use in the devices of the invention are known in the art.For example, injection ports, which can be subcutaneously implanted,have been described in, e.g., U.S. Pat. Nos. 4,816,016 and 4,681,560 toSchulte, and are commercially available (e.g., from C. R. Bard Co.). Aninjection port for implantation in vivo should be constructed ofmaterials that will not provoke an immune response or tissue reaction.An injection port preferably has an elastomeric seal secured to a baseand defining an injection chamber of predetermined volume. Theelastomeric seal can be adapted to sealingly engage a needle thatpierces the seal, e.g., a hypodermic needle, and to reseal when theneedle is removed, thereby preventing leakage. In general, preferredtreatment fluid receptacles can be readily and efficiently flushed witha small volume of flush fluid, e.g., can be flushed with less than about5 ml of flush fluid, more preferably less than about 2 ml, and stillmore preferably less than 1.5 ml. The amount of flush fluid requiredwill be determined, at least in part, by such factors as the totalvolume of the treatment fluid receptacle, the amount of "dead space" inthe treatment fluid receptacle, the nature of the treatment fluid andthe flush fluid, and the like. In preferred embodiments, the volume ofthe treatment fluid receptacle, e.g., the injection chamber, isminimized, e.g., has a small volume. By providing a small-volumetreatment fluid receptacle, the volume of treatment and flushing fluidsis minimized, preventing overinflation of the balloon and decreasing thevolume of fluids that must be handled by the physician. Preferredtreatment fluid receptacles have a volume of at least 0.5 ml, but notmore than 5 ml, more preferably between about 1 and about 3 ml. Ingeneral, it is desirable for the injection port to be palpable throughthe skin, so that it can be easily located. The treatment fluidreceptacle can be at least partially opaque to X-rays, permittinglocalization by radiography.

As mentioned above, in certain embodiments it is desirable, aftertreatment fluid has been injected into the treatment device, to flushthe injection port to displace a treatment fluid from the injection portand catheter. For example, when the treatment fluid is a radioactivefluid, it is desirable to prevent radiation damage to healthy tissueadjacent to the treatment fluid receptacle and along the catheter path.To prevent damage to healthy tissue, the treatment fluid can be flushedout of the injection port and away from such tissue. The flush fluid canbe flushed through the catheter and into the balloon, thereby flushingthe catheter and increasing the amount of radioactive material in theballoon. A small-volume treatment fluid receptacle can be flushedrapidly and completely using small volumes of flush solution, therebyreducing the amount of additional fluid added to the balloon. Thus, asmall-volume treatment fluid receptacle is preferred for use withradioactive treatment fluids. Alternatively, the flush fluid can beremoved from the treatment device, e.g., by use of a needle, positionedin the injection port, for withdrawing excess fluid. In this embodiment,two needles can be employed simultaneously: one needle for injection ofa flush fluid into the injection port, and a second needle for removalof the fluid. In this embodiment, further inflation of the balloon canbe prevented.

The inventive devices can include a diffusion barrier, to preventunwanted backflow of treatment fluid from the balloon into the catheter.The diffusion barrier thereby prevents premature deflation of theballoon and isolates the treatment fluid in the balloon. In particular,the diffusion barrier can reduce or prevent diffusion or flow of atreatment fluid, especially a radioactive treatment fluid, from theballoon into the catheter or other parts of the implantable device,thereby preventing damage to healthy tissue adjacent to the cathetertrack. The diffusion barrier can be any element or elements adapted toretard or prevent fluid flow, including, without limitation, a valve(e.g., a check valve) or other flow regulating element, a narrow flowsegment, and the like. A valve can be manually or automatically operatedto permit control of fluid flow, if desired, e.g., during balloonfilling, flushing of an injection port, or removal of fluid from thedevice. In certain embodiments, the diffusion barrier is an elastomericmaterial disposed in the fluid flow path and having a slit, e.g., a slitof proportions similar to a Holter valve opening. In this embodiment,fluid flow through the diffusion barrier can be accomplished by theapplication of fluid under pressure, e.g., by providing a fluid underpressure with a hypodermic syringe, causing the elastomer to yieldsufficiently to permit fluid flow. Preferably, the pressure required tocause fluid flow through the diffusion barrier is not so high as topresent risk of rupture of the therapeutic device, but is sufficient toreduce unwanted flow from the balloon. The diffusion barrier can provideresistance to fluid flow in one direction (e.g., a one-way check valve)or in both directions. However, the diffusion barrier is preferablyadapted to allow removal of fluid from the balloon when the therapeuticprocedure is complete, preferably without requiring removal of theballoon from the body cavity. Thus, in certain embodiments, thediffusion barrier is not a check valve. The diffusion barrier can reduceor eliminate flow from the balloon for at least a short period of time,e.g., sufficient time for therapeutic treatment to be completed.

In certain embodiments, the inventive apparatus can include a malleableelement extending through at least a portion of the length of thecatheter lumen. Thus, the malleable element is preferably adapted toconfer a shape upon at least a portion of the catheter length. Themalleable element is preferably an integral component of the catheter,and is not a stylet or guidewire. The malleable element can provideincreased stiffness to the catheter, thereby preventing kinking of thecatheter and concomitant blockage of the lumen, during insertion orremoval. In particular, the malleable element can eliminate the need fora separate guidewire or stylet for inserting the catheter, simplifyingsurgical procedures. However, the malleable element should not beexcessively rigid, to avoid damaging fragile tissues. The malleableelement further can permit a shape to be temporarily or permanentlyimparted to the catheter. Thus, the catheter can be easily andaccurately placed in the patient's body. For example, the malleableelement can be conformed to a shape of a body lumen, or can be formed topermit the balloon to be placed at a body site not readily accessible byconventional means. Also, the malleable element can provide a means forsecuring or anchoring the implantable device in a patient's body andpreventing the catheter from "backing out" during or after surgicalplacement.

The malleable element can comprise, a flexible wire, which can beembedded in a wall of the catheter, secured to an inner or outer surfaceof a sidewall of the catheter, or can be situated in the lumen of thecatheter. Thus, for example, FIG. 2A depicts a cross-sectional view ofone embodiment of a catheter along line 2--2 of FIG. 1. The sidewall 34of the catheter 26 defines a catheter lumen 36. A malleable wire 28 isembedded in the sidewall 34. FIG. 2B depicts a catheter in which amalleable element 28 is secured to the sidewall 34 in the catheter lumen36 of catheter 26. The wire can be made of, stainless steel, titaniumand other metals, and alloys thereof. A preferred malleable element is atitanium wire, e.g., a 20 mil annealed titanium wire. In one embodiment,the malleable element comprises a metallic element or alloy, such asnitinol, which exhibits "shape memory," i.e., has the property ofreturning to a predefined shape upon heating. In this embodiment, thewire can be selected to have a desired shape when implanted, but can bebent to a different shape prior to insertion to accommodate placement invivo, and then heated (e.g., with a resistive heater) to restore thepreselected shape. In certain preferred embodiments, the malleableelement comprises a metallic element or alloy which does notsubstantially interfere with NMR measurements, e.g., magnetic resonanceimaging; i.e., NMR measurements of the patient's body can be performedwhile the malleable element is present in the patient's body. In thisembodiment, non-ferromagnetic metals or alloys are preferred. Apreferred malleable element comprises an annealed titanium wire,preferably about 20 mil in diameter.

Such a wire can also be employed to provide a source of electriccurrent, e.g., to a resistive heater, or to provide means for monitoringconditions, e.g., temperature, inside the patient's body. Thus, amalleable wire can provide means for additional treatment modalities,e.g., heat therapy, which can be employed in conjunction withchemotherapy and brachytherapy, if desired. Additionally, the malleableelement can be employed as a radio-opaque marker for locating thecatheter in the body.

The inflatable treatment devices include an inflatable balloon forcontaining a treatment fluid in close proximity to the tissue to betreated. It will be understood that the term "balloon" is intended toinclude distensible devices which can be, but need not be, constructedof an elastic material. A variety of balloons or other distensibledevices for use with surgical catheters are known in the art and arecontemplated for use in the invention; many balloons are commerciallyavailable. In one embodiment, the balloon is constructed of a materialthat is substantially impermeable to the active components of thetreatment fluid with which it is filled, and is also impermeable to bodyfluids, e.g., blood, cerebrospinal fluid, and the like. An impermeableballoon is useful in conjunction with a radioactive treatment fluid, toprevent the radioactive material from escaping the treatment device andcontaminating the surgical field or tissues of the patient. In anotherembodiment, the balloon is permeable to the treatment fluid, and permitsthe fluid to pass out of the treatment device and into a body lumen orcavity. A permeable balloon is useful when the treatment fluid is achemotherapeutic agent which must contact tissue to be effective.Semi-permeable balloons can also find use in the inventive devices. Forexample, a semipermeable material that is capable of preventing thepassage of a radioactive material through the balloon wall can be usedto contain a radioactive treatment fluid, where certain fluid componentscan pass through the membrane while the radioactive component isretained within the balloon. In some embodiments, isotonic fluids arepreferred for use in semipermeable balloons, as discussed below.Silicone, e.g., NuSil, is a preferred material for a balloon wall.

In general, it is preferable that the balloon have a shape that permitsthe balloon to conform to the body cavity or lumen in which the balloonis to be inflated. For example, a generally spherical cavity can befilled with a substantially spherical balloon, while an elongatedballoon shape is suitable for an elongated body lumen such as a bloodvessel. Irregular balloon shapes may also find application in thesubject devices and methods. In certain embodiments, a balloon will beselected such that, upon inflation, the balloon does not compress thetissue which is being treated, or surrounding tissues. Thus, when aradioactive treatment fluid is introduced into the device, e.g., byinjection, the inflatable treatment device is inflated to a volume notsubstantially greater than a volume of the body cavity in which thedevice has been placed, thereby avoiding any substantial compression ordistortion of normal tissue. For example, in one embodiment, when theballoon is placed within a cavity left by surgical removal of tissue,the balloon is not inflated to a size substantially larger than the sizeof the cavity. However, in certain embodiments, the balloon preferablyis inflated to compress tissue. For example, when the proliferativedisorder being treated is, e.g., restenosis of a blood vessel, theballoon can be inflated to a size large enough to compress the excesstissue, while also providing chemotherapy, brachytherapy, or the like totreat the lesion. Thus, a balloon can be selected to have a desiredsize, and the amount of treatment fluid can be adjusted to attain aninflation of the balloon to achieve the desired size. In general, theballoon should have a small profile, e.g., a small size, when deflated,to permit facile placement in the patient's body and to minimize thesize of a surgical incision needed to place the balloon at the desiredsite of action.

In some embodiments, a balloon is attached to the catheter atsubstantially a single point on, or a single side of, the balloon body.Catheters suitable for use in the invention are well known in the art. Apreferred catheter material is radio-opaque silicone. Attachment of aballoon to a catheter at a single point on the balloon body permits theballoon (e.g., a spherical balloon) to maintain a substantially constant(e.g., spherical) shape over a range of inflation volumes. That is, theballoon is not constrained in shape by multiple attachment points to thecatheter, as is commonly the case with, e.g., balloons for Foleycatheters. In other embodiments, the balloon is attached to the catheterat multiple points on the balloon body, while allowing the balloon tomaintain a constant shape over a range of inflation sizes. For example,a balloon attached to a catheter at both distal and proximal points onthe balloon body can be unconstrained upon inflation where the catheterincludes an expansion element (e.g., a slidable engagement element) thatpermits the catheter to adjust in length as the balloon expands orcontracts. A balloon which maintains a substantially constant shape overa range of inflation volumes permits a surgeon to select a balloon toconform to a cavity of a particular shape with less concern over thesize of the cavity. Thus, devices that include such a balloon reduce theneed for the surgeon to prepare several different-sized balloons priorto surgery.

The invention also contemplates the use of multiple balloons, e.g., adouble-walled balloon. Such a balloon can comprise, for example, animpermeable inner wall and a permeable outer wall. In this embodiment,the inner balloon can be filled with, e.g., a radioactive treatmentfluid, while the outer balloon (i.e., the space between the inner andouter balloon walls) is filled with a chemotherapeutic treatment fluid.This embodiment allows two modes of therapy (e.g., chemotherapy andbrachytherapy) to be administered simultaneously with a single device.In this double-walled balloon embodiment, the device preferably includestwo treatment fluid receptacles, one in communication with each of thetwo balloons, preferably through a separate catheter, one catheterfluidly connected to each balloon and treatment fluid receptacle. Thetwo balloons can thus be inflated with two treatment fluids at the sametime or at different times during therapy. Inflation of an inner ballooncan provide pressure on an outer balloon, which can cause the outerballoon to expand, or can force or urge fluid in the space between theinner and outer balloon walls through the membrane of a porous outerballoon. Higher-order balloons, e.g., triple-walled balloons, can alsobe used in the inventive devices.

Thus, for example, FIG. 3 shows a double-balloon device of theinvention. The device has two treatment fluid receptacles 20, 21, eachhaving an elastomeric seal 22 secured thereto. Receptacle 20 is fluidlyconnected to outer balloon 24 through catheter 26, which includes amalleable element 28, and receptacle 21 is fluidly connected to innerballoon 40 by catheter 27, which includes diffusion barrier 32. Thedevice of FIG. 3 is useful where a chemotherapeutic fluid 30 is used toinflate the outer balloon 24, while a radioactive fluid 42 fills theinner balloon 40. Diffusion barrier 32 prevents flow of the radioactivefluid 42 from the balloon 40 to the catheter 27.

The catheter element can be any of a variety of catheters known in theart. A preferred catheter material is silicone, preferably a siliconethat is at least partially radio-opaque, thus facilitating x-raylocation of the catheter after implantation of the device. The cathetercan also include conventional adapters for attachment to the treatmentfluid receptacle and the balloon, as well as devices, e.g., right-angledevices, for conforming the catheter to contours of the patient's body.

In some embodiments, the inventive devices are provided in pre-assembledform, i.e., the components are assembled in advance of a surgicalinsertion procedure. In certain embodiments, however, the inventivedevices are configured to permit modular assembly of components, e.g.,by a surgeon. Thus, for example, a treatment fluid receptacle can beprovided with an element adapted for connection to any one of aplurality of catheters. The connection element can be, e.g., any elementknown in the art for effecting connection between components such ascatheters, injection ports, and the like. Illustrative connectorsinclude luer adapters and the like. In this embodiment, a variety ofcatheters and balloons can be provided, each of which is adapted forfacile connection to the treatment fluid receptacle. The surgeon canthen select an appropriate size and shape of balloon for treatment of aparticular proliferative disorder without need for providing severaltreatment fluid receptacles. The catheter and balloon can be selectedaccording to the results of pre-operative tests (e.g., x-ray, MRI, andthe like), or the selection can be made based on observation, during asurgical procedure, of the target cavity (e.g., a surgical cavityresulting from tumor excision). When the surgeon selects an appropriateballoon (e.g., a balloon having a size and shape suitable for placementin a body cavity), the catheter and balloon can then be attached to thepre-selected treatment fluid receptacle, thereby assembling thetreatment device.

The above-described implantable inflatable treatment devices can beemployed in the treatment of proliferative disorders in a patient. Inone aspect, the invention provides a method of treating proliferativedisorders including the step of implanting in the patient's body aninflatable treatment apparatus, in which the apparatus includes asmall-volume treatment fluid receptacle for receiving a treatment fluid;an inflatable balloon having a balloon body; a catheter connectedbetween the treatment fluid receptacle and the balloon and defining afluid flow path therebetween; and a diffusion barrier disposed in thefluid flow path between the treatment fluid receptacle and the balloon;wherein the balloon is secured to the catheter such that the balloonmaintains a substantially constant shape during inflation; andintroducing a treatment fluid into the treatment fluid receptacle sothat the balloon is inflated, such that the proliferative disorder istreated. In certain embodiments, the method includes the step ofselecting a balloon for treatment a proliferative disorder in a patient.In some embodiments, the method includes, prior to the implanting step,the further step of assembling an inflatable treatment apparatus.

The treatment devices of the invention (or any part thereof, e.g., theballoon) can be implanted according to surgical methods well known tothe skilled artisan. In one embodiment, the balloon is implanted in acavity formed by removal of tissue from a tumor or organ. Thus, incertain embodiments, the method includes the step of surgically removingtissue to form a cavity in the patient's body prior to implanting theinflatable device. In other embodiments, the device is implanted in anatural body cavity, e.g., in the abdominal cavity, or an organ such asa lung, uterus, or prostate gland. In yet other embodiments, a cavity orspace, for placement of the inventive device in a patient's body, can beformed by displacing, compressing, or otherwise repositioning tissue,without surgically removing tissue. Illustratively, tissue can becompressed, e.g., by inflation of a balloon, prior to placement of adevice of the invention in the cavity formed thereby. In certainembodiments, the treatment fluid receptacle is implanted subcutaneously.It will be appreciated that the catheter or catheters of the device canbe implanted so as to pass through a body wall, e.g., the skull, theabdominal wall, and the like.

The treatment fluid (or fluids) for inflating the balloon (or balloons)can be provided to the treatment fluid receptacle by, e.g.,transcutaneous injection into an injection port(s). Injection can bewith a syringe, e.g., a hypodermic syringe, or with a pump or othermechanical delivery means.

In certain preferred embodiments, the proliferative disorder is a tumor,more preferably a solid tumor, including both benign and malignanttumors. In some embodiments, the tumor is a cancerous tumor. Methods ofthe invention are useful in treating cancers such as, withoutlimitation, brain tumors, breast tumors, prostate tumors, ovariantumors, and the like. In another preferred embodiment, the proliferativedisorder is restenosis, e.g., of a blood vessel. Thus, the subjectmethod can be employed to treat or to prevent restenosis in a patient.Similarly, the subject method can be employed to treat hyperplasia,including endometriosis, benign prostatic hyperplasia, and the like.

In certain embodiments, the treatment fluid includes a chemotherapyagent. Formulation and dosage of chemotherapy agents is routine to theskilled artisan. In certain embodiments, the treatment fluid includes aradioisotope. Radioactive treatment fluids are useful for brachytherapy,as discussed supra. Preferred radioisotopes for brachytherapy include ⁹⁰Y, ¹⁹⁸ Au, ³² P, ¹²⁵ I, and ¹³¹ I. Radioisotope preparations suitablefor use in the subject treatment devices are known to those of skill inthe art. It will be appreciated that a treatment fluid can be formulatedto provide more than one treatment modality. For example, a chemotherapyfluid can be heated to provide both chemotherapy and heat therapy. Incertain embodiments, the treatment fluid is approximately isotonic withbody fluids; that is, the tonicity (ionic strength) of the treatmentfluid is close to that of physiological fluids. Use of isotonictreatment fluids avoids transfer of solutions across the balloon bodymembrane, thereby preventing unexpected or undesired inflation ordeflation of the balloon, or dilution or concentration of the treatmentfluid.

In certain embodiments, the method of treatment includes the furtherstep of flushing the treatment fluid receptacle (e.g., the injectionport) with a flush fluid. As previously described, it is important toavoid damaging healthy tissue by exposure to high doses of radiationfrom the treatment fluid. Thus, to prevent damage to tissue adjacent theinjection port and the catheter, the injection port and catheter can beflushed with a non-radioactive flush fluid. In certain embodiments, theflush fluid is flushed into the balloon. In this embodiment, the volumeof flush fluid should be carefully regulated to ensure that the balloondoes not become overinflated. In certain embodiments, the flush fluidinflates the balloon by no more than 20%, more preferably no more than10%. Alternatively, the flush fluid can be withdrawn from the treatmentdevice, e.g., by removal with a needle introduced into the injectionport. In this embodiment, the balloon is preferably not significantlyfurther inflated, e.g., inflation due to the flush solution is less than10%, more preferably less than 5%, of the volume of the inflatedballoon. In some preferred embodiments, e.g., where a radioactivetreatment fluid has been employed, the flushing step can reduce thelevel of radioactivity present in the treatment fluid receptacle or thecatheter by at least about 50%, more preferably by at least 80%, andstill more preferably by at least 90%.

In certain embodiments, the flush solution has approximatelyphysiological tonicity. In some embodiments, the flush solution is moreviscous than the treatment fluid such that the flow of the flush fluidapproaches plug flow. A viscous flush solution can also prevent backflowor diffusion of a radioactive treatment fluid because the higherviscosity impedes flow in the catheter lumen.

The treatment is preferably continued until the proliferative disorderhas been significantly ameliorated, e.g., if the proliferative disorderis a tumor, treatment is continued until the tumor has decreased in sizeby at least about 10%, more preferably at least about 20%. Theinflatable device can be left in place and repeated filled withtreatment fluid, if desired. For example, repeated doses of achemotherapy fluid can be administered without disturbing the placementof the device, simply by injecting more treatment fluid into a permeableballoon after-the original dose has passed through he balloon.Similarly, a radioactive fluid can be removed, e.g., to preventexcessive doses of radiation or when the radioisotope has decayed, andreplenished by addition of fresh radioisotope solution. Where it isdesired to use repeated doses, the strength of the doses can be varied,for example, a first, strong dose, followed by a second, less potentdose. Determination of appropriate dosages strengths and treatmentregimens will be routine for the skilled artisan.

The contents of each patent, patent application, and publication citedherein are hereby incorporated by reference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to themethods and devices described herein. Such equivalents are considered tobe within the scope of this invention and are covered by the followingclaims.

What is claimed is:
 1. An implantable apparatus for treating aproliferative disorder in a patient, comprising:a treatment fluidreceptacle for receiving a treatment fluid; an inflatable balloon havinga balloon body; a catheter connected between the treatment fluidreceptacle and the balloon and defining a fluid flow path therebetween;and a diffusion barrier disposed in the fluid flow path between thetreatment fluid receptacle and the balloon.
 2. The apparatus of claim 1,wherein the treatment fluid receptacle has a small volume and is adaptedto be implanted subcutaneously in the body of the patient.
 3. Theapparatus of claim 1, wherein the diffusion barrier is a narrow flowsegment.
 4. The apparatus of claim 1, wherein the balloon has asubstantially spherical shape when inflated.
 5. The apparatus of claim1, wherein the balloon is secured to the catheter at substantially asingle point on the balloon body.
 6. The apparatus of claim 1, whereinthe balloon is secured to the catheter at a plurality of points on theballoon body.
 7. The apparatus of claim 1, wherein the catheter furthercomprises a malleable element.
 8. The apparatus of claim 1, wherein theballoon body is substantially impermeable to the treatment fluid.
 9. Theapparatus of claim 1, wherein the balloon comprises a semipermeablemembrane.
 10. The apparatus of claim 1, wherein the treatment fluidreceptacle is sized and dimensioned for being flushed with a flushingfluid without substantially expanding the balloon.
 11. The apparatus ofclaim 1, wherein the balloon is secured to the catheter such that theballoon maintains a pre-selected shape during inflation.
 12. Theapparatus of claim 1, wherein the balloon comprises a double-walledballoon having an inner wall and an outer wall.
 13. The apparatus ofclaim 1, wherein the balloon is sized and dimensioned for placement in ablood vessel.
 14. The apparatus of claim 1, wherein the balloon is sizedand dimensioned for placement in a cavity left by surgical removal of atumor from the patient.
 15. The apparatus of claim 1, wherein theballoon is sized and dimensioned for placement in a natural body cavity.16. The apparatus of claim 1, wherein the balloon is filled with atreatment fluid.
 17. The apparatus of claim 16, wherein the treatmentfluid is a radioactive fluid.
 18. The apparatus of claim 16, wherein thetreatment fluid has substantially physiological tonicity.
 19. Theapparatus of claim 12, further comprising a second treatment fluidreceptacle.
 20. The apparatus of claim 19, wherein the second treatmentfluid receptacle fluidly communicates with a volume between inner andouter balloon walls.
 21. An implantable apparatus for treating aproliferative disorder in a patient, comprising:a treatment fluidreceptacle for receiving a treatment fluid; an inflatable balloon havinga balloon body; and a catheter connected between the treatment fluidreceptacle and the balloon and defining a fluid flow path therebetween;wherein the catheter further comprises a malleable element.
 22. Theapparatus of claim 21, wherein the malleable element does notsubstantially interfere with NMR analysis.
 23. The apparatus of claim21, wherein the balloon is sized and dimensioned for placement in ablood vessel.
 24. An implantable apparatus for treating a proliferativedisorder in a patient, comprising:a treatment fluid receptacle forreceiving a treatment fluid; an inflatable balloon having a balloonbody; a catheter connected between the treatment fluid receptacle andthe balloon and defining a fluid flow path therebetween; and a diffusionbarrier disposed in the fluid flow path between the treatment fluidreceptacle and the balloon; wherein the treatment fluid receptacle isadapted to be flushed with a small volume of a flush fluid.
 25. A methodfor treating a proliferative disorder in a patient, the methodcomprising the steps of:implanting in the patient's body an inflatabletreatment apparatus, the apparatus comprising:a treatment fluidreceptacle for receiving a treatment fluid; an inflatable balloon havinga balloon body; a catheter connected between the treatment fluidreceptacle and the balloon and defining a fluid flow path therebetween;and a diffusion barrier disposed in the fluid flow path between thetreatment fluid receptacle and the balloon; and introducing a treatmentfluid into the treatment fluid receptacle such that the balloon isinflated; such that the proliferative disorder is treated.
 26. Themethod of claim 25, further comprising the step of flushing thetreatment fluid into the balloon.
 27. The method of claim 25, whereinthe treatment fluid is flushed into the balloon with a flush fluid. 28.The method of claim 27 wherein the flush fluid further inflates theballoon by no more than 10% of the balloon volume prior to the flushingstep.
 29. The method of claim 25, wherein the implanting step comprisesthe step of positioning the inflatable balloon adjacent to a tumor. 30.The method of claim 29, wherein the implanting step comprises the stepof positioning the inflatable balloon adjacent to a solid tumor.
 31. Themethod of claim 29, wherein the implanting step comprises the step ofpositioning the inflatable balloon adjacent to a cancerous tumor. 32.The method of claim 29, wherein the implanting step comprises the stepof positioning the inflatable balloon adjacent to a brain tumor.
 33. Themethod of claim 29, wherein the implanting step comprises the step ofpositioning the inflatable balloon adjacent to a breast tumor.
 34. Themethod of claim 25, further comprising, prior to the implanting step,the step of surgically creating a cavity in the patient's body.
 35. Themethod of claim 25, further comprising, prior to the implanting step,the step of selecting a balloon for treating the proliferative disorder.36. The method of claim 35, further comprising, prior to the implantingstep, the step of assembling the inflatable treatment apparatus.
 37. Themethod of claim 25, wherein the apparatus is implanted in a natural bodycavity.
 38. A method for treating a proliferative disorder in a patient,the method comprising:determining a characteristic of a cavity in thepatient's body, the characteristic being selected from the groupconsisting of volume, shape, or a dimension; selecting an inflatableballoon suitable for placement in the cavity, the balloon including aballoon body; implanting in the cavity an inflatable treatment apparatuscomprising:a treatment fluid receptacle for receiving a treatment fluid;the inflatable balloon; a catheter connected between the treatment fluidreceptacle and the balloon and defining a fluid flow path therebetween;a diffusion barrier disposed in the fluid flow path between thetreatment fluid receptacle and the balloon; and introducing a treatmentfluid into the treatment fluid receptacle such that the balloon isinflated; such that the proliferative disorder is treated.
 39. Themethod of claim 38, wherein the treatment fluid is a radioactive fluid.40. The method of claim 38, wherein the treatment fluid is achemotherapy fluid.
 41. The method of claim 38, the method comprising,prior to the implanting step, the further step of assembling theinflatable treatment apparatus.
 42. An implantable apparatus fortreating a proliferative disorder in a patient, said apparatuscomprising:a treatment fluid receptacle for receiving a treatment fluid;an inflatable balloon having a balloon body; a catheter connectedbetween said treatment fluid receptacle and said balloon, said catheterdefining a fluid flow path therebetween; and a narrow flow segmentdisposed in said fluid flow path between said treatment fluid receptacleand said balloon.
 43. An implantable apparatus for treating aproliferative disorder in a patient, said apparatus comprising:atreatment fluid receptacle for receiving a treatment fluid; aninflatable balloon having a balloon body; a catheter connected betweensaid treatment fluid receptacle and said balloon, said catheter defininga fluid flow path therebetween; a malleable element coupled to saidcatheter, and a diffusion barrier disposed in the fluid flow pathbetween said treatment fluid receptacle and said balloon.